Aims Renal denervation (RDN) is widely investigated in multiple studies of sympathetically driven cardiovascular diseases. While the therapeutic potential of RDN for ventricular arrhythmia has been reported, the mechanisms responsible for its antiarrhythmic effect are poorly understood. Our recent study showed that macrophage expansion-induced neuroinflammation in the stellate ganglion (SG) was a critical factor for cardiac sympathetic overactivation and ventricular arrhythmogenesis in chronic heart failure (CHF). This study investigates if and how RDN decreases ventricular arrhythmias by attenuating neuroinflammation in cardiac sympathetic post-ganglionic (CSP) neurons in CHF. Methods and results Rat CHF was induced by surgical ligation of the left anterior descending (LAD) coronary artery. At 12 weeks after LAD ligation, completed bilateral RDN was achieved by surgically cutting all the visible renal nerves around the renal artery and vein, followed by applying 70% ethanol around the vessels. Immunofluorescence staining and western blot data showed that expression of granulocyte-macrophage colony-stimulating factor (GM-CSF) and its receptor-α subunit in SGs was increased in CHF rats. RDN not only reduced CHF-elevated GM-CSF levels in kidney, serum, and SGs but also attenuated macrophage expansion and neuroinflammation in SGs from CHF rats. Using flow cytometry, we confirmed that RDN reduced the percentage of macrophages in SGs, which is pathologically increased in CHF. RDN also decreased CHF-enhanced N-type Ca2+ currents in CSP neurons and attenuated CHF-elevated cardiac sympathetic nerve activity. Electrocardiogram data from 24-h continuous telemetry recording in conscious rats revealed that RDN improved CHF-induced heterogeneity of ventricular electrical activities and reduced the duration of spontaneous ventricular tachyarrhythmias in CHF rats. Conclusion RDN alleviates cardiac sympathetic overactivation and ventricular arrhythmogenesis through attenuating GM-CSF-induced macrophage activation and neuroinflammation within SGs in CHF. This suggests that manipulation of the GM-CSF signalling pathway could be a novel strategy for achieving the antiarrhythmic effect of RDN in CHF.

中文翻译：

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肾去神经支配通过减弱慢性心力衰竭中星状神经节的巨噬细胞活化和神经炎症来实现抗心律失常作用


目的 肾去神经术 (RDN) 在交感神经驱动的心血管疾病的多项研究中得到广泛研究。虽然 RDN 对室性心律失常的治疗潜力已有报道，但其抗心律失常作用的机制却知之甚少。我们最近的研究表明，巨噬细胞扩张引起的星状神经节（SG）神经炎症是慢性心力衰竭（CHF）中心脏交感神经过度激活和室性心律失常发生的关键因素。本研究探讨 RDN 是否以及如何通过减轻 CHF 患者心脏交感神经节后 (CSP) 神经元的神经炎症来减少室性心律失常。方法和结果通过手术结扎左冠状动脉前降支（LAD）诱导大鼠CHF。 LAD结扎后12周，通过手术切除肾动脉和静脉周围所有可见的肾神经，然后在血管周围涂抹70%乙醇，实现了完整的双侧RDN。免疫荧光染色和蛋白质印迹数据显示，CHF 大鼠 SG 中粒细胞巨噬细胞集落刺激因子 (GM-CSF) 及其受体 α 亚基的表达增加。 RDN 不仅降低了肾脏、血清和 SG 中因 CHF 升高的 GM-CSF 水平，而且还减弱了 CHF 大鼠 SG 中的巨噬细胞扩张和神经炎症。使用流式细胞术，我们证实 RDN 降低了 SG 中巨噬细胞的百分比，而 CHF 中巨噬细胞的百分比病理性增加。 RDN 还降低了 CSP 神经元中 CHF 增强的 N 型 Ca2+ 电流，并减弱了 CHF 升高的心脏交感神经活动。 清醒大鼠 24 小时连续遥测记录的心电图数据显示，RDN 改善了 CHF 诱导的心室电活动的不均匀性，并减少了 CHF 大鼠自发性室性快速心律失常的持续时间。结论 RDN 通过减弱 CHF 中 GM-CSF 诱导的巨噬细胞活化和 SG 内的神经炎症来减轻心脏交感神经过度激活和室性心律失常发生。这表明操纵 GM-CSF 信号通路可能是实现 RDN 在 CHF 中抗心律失常作用的新策略。